Citation and License

Abstract

Background

Allosteric communications are vital for cellular signaling. Here we explore a relationship
between protein architectural organization and shortcuts in signaling pathways.

Results

We show that protein domains consist of modules interconnected by residues that mediate
signaling through the shortest pathways. These mediating residues tend to be located
at the inter-modular boundaries, which are more rigid and display a larger number
of long-range interactions than intra-modular regions. The inter-modular boundaries
contain most of the residues centrally conserved in the protein fold, which may be
crucial for information transfer between amino acids. Our approach to modular decomposition
relies on a representation of protein structures as residue-interacting networks,
and removal of the most central residue contacts, which are assumed to be crucial
for allosteric communications. The modular decomposition of 100 multi-domain protein
structures indicates that modules constitute the building blocks of domains. The analysis
of 13 allosteric proteins revealed that modules characterize experimentally identified
functional regions. Based on the study of an additional functionally annotated dataset
of 115 proteins, we propose that high-modularity modules include functional sites
and are the basic functional units. We provide examples (the Gαs subunit and P450 cytochromes) to illustrate that the modular architecture of active
sites is linked to their functional specialization.

Conclusion

Our method decomposes protein structures into modules, allowing the study of signal
transmission between functional sites. A modular configuration might be advantageous:
it allows signaling proteins to expand their regulatory linkages and may elicit a
broader range of control mechanisms either via modular combinations or through modulation
of inter-modular linkages.